Sleep apnea is the cessation of breathing for at least 10 seconds, whereas 50% to 80% reduction in airflow for significant periods during sleep is called hypopnea. These events are accompanied with reduction in oxygen (O2) saturation, increase in arterial pressure and decrease in heart rate. Apneic and hypopneic events are combined into the apneic/hypopneic index (AHI), which is the total number of apneic/hypopneic events per hour of sleep. AHI is usually of 10 or more in sleep apnea.
There are 3 types of sleep apnea: obstructive sleep apnea (OSA), central sleep apnea (CSA) and mixed sleep apnea which has both OSA and CSA as components.
Obstructive sleep apnea (OSA) is due to the occlusion of the airways leading to ineffective respiratory efforts during sleep. OSA is often associated with obesity. Its hallmark clinical symptom is excessive snoring which abruptly ceases during the apneic episodes and the brief period of patient arousal and then resumes when the patient again falls asleep. This may cause excessive daytime sleepiness that can lead to impairment of almost any daytime activity (sleep apnea syndrome).
Central sleep apnea (CSA), which is rare, is usually due to central nervous system dysfunction and causes no respiratory effort.
The most common treatment for patients with severe sleep apnea is continuous positive airway pressure (CPAP), usually through a nasal mask, during sleep. There is no evidence, apart from major weight reduction or abstinence from alcohol, that simple, non-invasive lifestyle changes improve sleep apnea or its consequences.
On the other hand, fibrates have been reported to lower plasma triglycerides and cholesterol levels and to be beneficial in the prevention of ischemic heart disease in individuals with elevated levels of LDL cholesterol. They can also decrease to some extent elevated fibrinogen and PAI-1 levels. Fibrate compounds can also elevate the level of plasma HDL cholesterol.
In the present invention, fibrates are defined as PPARα agonists (peroxisome proliferator activated receptor alpha agonists), including fibric acid derivatives (e.g. fenofibric acid or clofibric acid) and pharmaceutically acceptable salts and esters of such fibric acid derivatives.
Fibrate compounds include, but are not limited to, gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, and analogs, derivatives and pharmaceutically acceptable salts thereof.
According to the present invention, the preferred fibrate is fenofibrate, fenofibric acid (active metabolite of fenofibrate) and/or a salt of fenofibric acid, in particular photostable salts of fenofibric acid as described in U.S. Pat. No. 7,259,186, especially choline, ethanolamine, diethanolamine, piperazine, calcium and tromethamine salts of fenofibric acid.
Fenofibrate has been commercially available in Europe (Lipanthyl®) since 1975 and in the USA (TriCor®) since 1998.
Fenofibrate is indicated as adjunct therapy to diet for the treatment of patients with primary hypercholesterolemia (Fredrickson Type IIa) or mixed dyslipidemia (Fredrickson Type IIb). Fenofibrate is also indicated as adjunctive therapy to diet for treatment of adult patient with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). The effects of fenofibrate observed in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein ilipase and reducing production of apolipoprotein CIII (an inhibitor of lipoprotein lipase activity).
Fenofibrate also decreased plasma fibrinogen levels in normolipidemic patients and in dyslipidemic patients. The fibrinogen-lowering effect of fenofibrate was shown to be in the range −7% to −17%. This reduction of fibrinogen was accompanied by a reduction in other acute phase proteins such as interleukin 6 and C reactive protein.
Fenofibrate is virtually insoluble in water, which limits its absorption and contributes to a significant increase in exposure when administered with food. The absorption of fenofibrate, as currently marketed in Europe (tablets 160 mg and micronized capsules 67 mg, 200 mg and 267 mg dose strengths), is subject to substantial food effects. When the 160 mg tablet is administered with food, exposure to fenofibric acid, the active metabolite of fenofibrate, is increased by 35% compared to administration under fasting conditions. In order to improve convenience for patients, a fenofibrate tablet formulation has been developed which is devoid of food effect and may be taken without regard to meals. This new tablet formulation, based on a further reduction of fenofibrate particle size using a NanoCrystal® technology also allows a lower strength tablet (145 mg) to provide fenofibric acid exposure equivalent to that from the reference 200 mg micronized fenofibrate capsules and 160 mg tablet.